Severe malaria kills about 900,000 children a year and impairs brain function in some survivors. Human CM (HCM) is a severe form of malaria characterized by sequestration of parasitized red blood cells (pRBCs) in cerebral micro-circulation and induction of inflammatory mediators which cause impaired consciousness with unarousable coma. We reported [PLoS One, 2012;7(3):e34280)] that excess production of heme, a by-product of Plasmodium berghei-damaged erythrocytes during infection, is a major cause of inflammation, loss of blood brain barrier (BBB) integrity and tissue damage associated with fatal experimental cerebral malaria (ECM) . Excess free heme induces up-regulation of STAT3 and CXCL10 whereas up-regulation of HO-1, an essential enzyme in heme catabolism, limits sequestration of pRBC, induction of inflammatory mediators and brain tissue damage caused by ECM. Following a screen for agents that attenuate ECM, we identified Neuregulin- 1(NRG-1), a 8 kDa peptide currently undergoing clinical trials for use against traumatic brain injury, that attenuates mortality, limits sequestration of pRBC, induces anti-inflammatory mediators and reduces brain tissue damage in ECM when delivered intravenously or intra-peritoneally at 5g/kg (J Neuro,2014:11:9). NRG- 1 mediated attenuation of mortality was via perturbation of expression of a network of pro-inflammatory and anti-inflammatory factors during ECM pathogenesis. We observed that ECM resistant mice (BALB/c) constitutively expressed higher levels of NRG-1 in brain tissue than ECM susceptible (C57BL/6) mice. In human malaria, serum NRG-1 was higher in mild malaria cases but lowest in fatal HCM indicating a possible inhibitory role of infection on endogenous serum NRG-1 production. Expression of NRG-1 in brain tissue, on the other hand, was dependent on expression of ErbB4, a NRG-1 receptor, in damaged brain regions. Since NRG-1 negatively regulates STAT3 and CXCL10 (a key biological determinant of fatal ECM) and positively regulates HO-1, our goal is to functionally assess the key pathways perturbed by NRG-1 to attenuate ECM and HCM pathogenesis. Our main hypothesis is that NRG-1 attenuates CM mortality by down regulating CXCL10 and STAT3 activation and up regulating HO-1. The proposed study focuses on the mechanism by which NRG- 1 regulates the heme-STAT3-CXCL10-HO-1 system to protect against fatal ECM. Three specific aims are proposed. Specific Aim 1: will test the hypothesis that NRG-1 is essential for protection of brain microvascular endothelium and blood-brain barrier (BBB) against heme-induced damage in human CM pathogenesis. Specific Aim 2: will test the hypothesis that NRG-1 is essential for protection against ECM-induced CNS damage and neurobehavioral outcomes via heme-STAT3-CXCL10-HO-1 signaling pathway. Specific Aim 3: will test the hypothesis that NRG-1 attenuates severe HCM by restoring integrity of human blood-brain barrier. Understanding the protective effect of NRG-1 against CM pathogenesis and mortality will provide opportunities for discovery of a new class of small molecule adjunctive therapeutics and interventions against fatal CM.